Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine & School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.
J Chem Inf Model. 2022 May 23;62(10):2421-2431. doi: 10.1021/acs.jcim.2c00074. Epub 2022 May 5.
Docosahexaenoic acid (DHA) is a ω-3 polyunsaturated fatty acid, which can be uptaken by cells and is essential for proper neuronal and retinal function. However, the detailed physical impact of DHA molecules on the plasma membrane is still unclear. Hence, in this work, we carried out μs-scale coarse-grained molecular dynamics (MD) simulations to reveal the interactions between DHA molecules and a model cell membrane. As is known, the cell membrane can segregate into liquid-ordered () and liquid-disordered () membrane domains due to the differential interactions between lipids and proteins. In order to capture this feature, we adopted the three-component phase-separated lipid membranes and considered both anionic and neutral DHA molecules in the current work. Our results showed that DHA molecules can spontaneously self-assemble into nanoclusters, fuse with lipid membranes, and localize preferably in membrane domains. During the membrane fusion process, DHA molecules can change the intrinsic transmembrane potential of the lipid membrane, and the effects of anionic DHA molecules are much more significant. Besides, the presence of DHA molecules mainly in the membrane domains could regulate the differences in the lipid chain order, membrane thickness, cholesterol preference, and cholesterol flip-flop basically in a concentration-dependent manner, which further promote the stability of the intraleaflet dynamics and inhibit the interleaflet dynamics (or promote membrane domain registration) of the membrane domains. In short, the impact of DHA molecules on the physical properties of a model cell membrane on the molecular level revealed in our work will provide useful insights for understanding the biological functions of DHA molecules.
二十二碳六烯酸（DHA）是一种 ω-3 多不饱和脂肪酸，可被细胞摄取，对神经元和视网膜的正常功能至关重要。然而，DHA 分子对质膜的详细物理影响仍不清楚。因此，在这项工作中，我们进行了微秒尺度的粗粒分子动力学（MD）模拟，以揭示 DHA 分子与模型细胞膜之间的相互作用。众所周知，由于脂质和蛋白质之间的相互作用不同，细胞膜可以分离成有序（）和无序（）的膜域。为了捕捉到这一特征，我们采用了三组分相分离脂质膜，并在当前的工作中考虑了阴离子和中性 DHA 分子。我们的结果表明，DHA 分子可以自发地自组装成纳米团簇，与脂质膜融合，并优先定位于 膜域。在膜融合过程中，DHA 分子可以改变脂质膜的固有跨膜电位，而阴离子 DHA 分子的影响更为显著。此外，DHA 分子主要存在于 膜域中，可以基本以浓度依赖的方式调节脂质链有序性、膜厚度、胆固醇偏好和胆固醇翻转的差异，从而进一步促进膜域内叶层动力学的稳定性，并抑制膜域的叶层间动力学（或促进膜域配准）。总之，我们在工作中揭示了 DHA 分子对模型细胞膜物理性质的影响，这为理解 DHA 分子的生物学功能提供了有用的见解。
